{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:28:33Z","timestamp":1785817713586,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII)","award":["PI20\/00110"],"award-info":[{"award-number":["PI20\/00110"]}]},{"name":"European Union","award":["PI20\/00110"],"award-info":[{"award-number":["PI20\/00110"]}]},{"name":"Spanish Ministry of Science and Innovation","award":["PI20\/00110"],"award-info":[{"award-number":["PI20\/00110"]}]},{"name":"Regional Development European Funds (European Union)","award":["PI20\/00110"],"award-info":[{"award-number":["PI20\/00110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (&lt;30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G&gt;A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).<\/jats:p>","DOI":"10.3390\/genes14020502","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T02:28:27Z","timestamp":1676514507000},"page":"502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in BRCA2"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-4767","authenticated-orcid":false,"given":"Irene","family":"Hidalgo Mayoral","sequence":"first","affiliation":[{"name":"Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Almeida Santiago","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-4430","authenticated-orcid":false,"given":"Jose Manuel","family":"S\u00e1nchez-Zapardiel","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Hidalgo Calero","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8113-1410","authenticated-orcid":false,"given":"Miguel","family":"de la Hoya","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos, Hospital Universitario Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"G\u00f3mez-Sanz","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos, Hospital Universitario Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"de Miguel Reyes","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Robles","sequence":"additional","affiliation":[{"name":"Medical Oncology Service, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/s41436-019-0554-6","article-title":"Meta-analysis and multidisciplinary consensus statement: Exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders","volume":"21","author":"Srivastava","year":"2019","journal-title":"Genet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/bjc.2015.14","article-title":"Low-level constitutional mosaicism of a de novoBRCA1 gene mutation","volume":"112","author":"Friedman","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s10689-020-00186-1","article-title":"Constitutional mosaicism for a BRCA2 mutation as a cause of early-onset breast cancer","volume":"19","author":"Alhopuro","year":"2020","journal-title":"Fam. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/s41436-020-0877-3","article-title":"A six-attribute classification of genetic mosaicism","volume":"22","author":"Tenorio","year":"2020","journal-title":"Genet. Med."},{"key":"ref_5","unstructured":"Carlson, B. (1999). Human Embriology & Developmental Biology, Elsevier. [4th ed.]."},{"key":"ref_6","first-page":"428","article-title":"Mosaicism: Implications for genetic counseling and medical management","volume":"21","author":"Waldman","year":"2017","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1146\/annurev-genom-120121-105450","article-title":"Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk","volume":"23","author":"Chen","year":"2022","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/cge.12057","article-title":"A germline mosaic BRCA1 exon deletion in a woman with bilateral basal-like breast cancer","volume":"84","author":"Delon","year":"2013","journal-title":"Clin Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/onc.2015.181","article-title":"Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations","volume":"35","author":"Golmard","year":"2016","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gr\u00e1f, A., Enyedi, M.Z., Pint\u00e9r, L., Kriston-P\u00e1l, \u00c9., Jaksa, G., B\u00e1lind, \u00c1., Ezer, \u00c9., Horv\u00e1th, P., S\u00fck\u00f6sd, F., and Kiss, E. (2021). The combination of single-cell and next-generation sequencing can reveal mosaicism for BRCA2 mutations and the fine molecular details of tumorigenesis. Cancers, 13.","DOI":"10.3390\/cancers13102354"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13053-022-00237-x","article-title":"Low\u2014level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer","volume":"20","author":"Speight","year":"2022","journal-title":"Hered. Cancer Clin. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1136\/jmedgenet-2017-105188","article-title":"Consensus for genes to be included on cancer panel tests offered by UK genetics services: Guidelines of the UK Cancer Genetics Group","volume":"55","author":"Taylor","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"Mutationtaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1101\/gr.097857.109","article-title":"Detection of nonneutral substitution rates on mammalian phylogenies","volume":"20","author":"Pollard","year":"2010","journal-title":"Genome Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.jmoldx.2020.02.001","article-title":"The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism","volume":"22","author":"Brewer","year":"2020","journal-title":"J. Mol. Diagn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.jmoldx.2016.07.006","article-title":"Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing","volume":"18","author":"Mu","year":"2016","journal-title":"J. Mol. Diagn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/cmb.1997.4.311","article-title":"Improved Splice Site Detection in Genie","volume":"4","author":"Reese","year":"1997","journal-title":"J. Comput. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/nar\/29.5.1185","article-title":"GeneSplicer: A new computational method for splice site prediction","volume":"29","author":"Pertea","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/sj.bjc.6601894","article-title":"The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website","volume":"91","author":"Bamford","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0096531","article-title":"A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing","volume":"9","author":"Behjati","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/humu.22488","article-title":"Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing","volume":"35","author":"Chen","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/cge.14202","article-title":"Looking closely at overgrowth: Constitutional mosaicism in PTEN hamartoma tumor syndrome","volume":"102","author":"Newman","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10689-018-0072-8","article-title":"APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis","volume":"17","author":"Stormorken","year":"2018","journal-title":"Fam. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41467-018-06581-8","article-title":"Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls","volume":"9","author":"Momozawa","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Andreassen, P.R., Seo, J., Wiek, C., and Hanenberg, H. (2021). Understanding BRCA2 function as a tumor suppressor based on domain-specific activities in DNA damage responses. Genes, 12.","DOI":"10.3390\/genes12071034"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1126\/science.297.5588.1837","article-title":"BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure","volume":"297","author":"Yang","year":"2002","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1038\/s41436-020-0814-5","article-title":"Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2","volume":"22","author":"Mesman","year":"2020","journal-title":"Genet. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/humu.23626","article-title":"Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI)","volume":"39","author":"Pesaran","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines","volume":"41","author":"Tavtigian","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nature21703","article-title":"Somatic mutations reveal asymmetric cellular dynamics in the early human embryo","volume":"543","author":"Ju","year":"2017","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.tig.2015.03.013","article-title":"Somatic mosaicism: Implications for disease and transmission genetics","volume":"31","author":"Campbell","year":"2015","journal-title":"Trends Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s12094-019-02262-0","article-title":"SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)","volume":"22","author":"Aguirre","year":"2020","journal-title":"Clin. Transl. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrg3424","article-title":"A genomic view of mosaicism and human disease","volume":"14","author":"Biesecker","year":"2013","journal-title":"Nat. Rev. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:10Z","timestamp":1760121430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,15]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020502"],"URL":"https:\/\/doi.org\/10.3390\/genes14020502","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,15]]}}}